Myocardial oxygen delivery is intimately dependent on regulation of tone in coronary resistance vessels. We have found that different segments within the coronary microcirculation exhibit non-uniform vascular reactions to a given stimulus. This implies that there are different regulatory mechanisms at different levels within the coronal microcirculation. The overall goal of this proposal is to specifically document the predominant regulatory mechanisms of large and small coronary arterial vessels. We plan to examine extrinsic and intrinsic control mechanisms at different levels in the coronary circulation. These studies will be accomplished in the beating heart, using a system that compensates for cardiac motion and enables measurements of microvascular diameters and pressures in the subepicardial microcirculation. Also, we plan to extend the above mentioned studies to the subendocardium. This will be accomplished by studying isolated arterioles from different locations within the left ventricular wall. We will test five specific hypotheses in this proposal: 1) alpha-Adrenergic coronary constriction and metabolic coronary dilation occur at different microvascular levels. 2) During alpha- adrenergic activation in the coronary circulation, small arteriolar vasodilation is related to the production of a vasoactive metabolite. 3) Small coronary arterioles are responsive to alpha- adrenergic stimuli, if their intrinsic autoregulatory adjustments are abolished. 4) alpha-Adrenergic sensitivity of isolated subendocardial arterioles is less than that in similarly sized arterioles from the subepicardium. 5) Small coronary microvessels have intrinsic myogenic responses and these responses will be, in part, dependent on the presence of a functionally intact endothelium. Unique information towards understanding regulatory factors at different levels in the microcirculation, and how integration at different levels optimizes oxygen delivery will be elucidated by this proposal. This information is essential towards a more complete understanding of disorders (pathophysiology) of myocardial oxygen delivery in the myocardium.